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Re-evaluating the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein crosslinking with Michael acceptor motif-containing drugs

Abstract:

Deubiquitinating enzymes are a growing target class across multiple disease states, with several inhibitors now report-ed. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight complexes. Activity-based proteome profiling identified CIAPIN1 as a sub-micromolar covalent target of VLX1570, and further analysis demonstrated...

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Publication status:
Published
Peer review status:
Peer reviewed

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Publisher copy:
10.1021/acs.jmedchem.0c00144

Authors


More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDM
Sub department:
Target Discovery Institute
Role:
Author
ORCID:
0000-0002-8735-5263
More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDM
Sub department:
Target Discovery Institute
Role:
Author
More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDM
Sub department:
Target Discovery Institute
Role:
Author
More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDM
Sub department:
Structural Genomics Consortium
Role:
Author
Publisher:
American Chemical Society Publisher's website
Journal:
Journal of Medicinal Chemistry Journal website
Volume:
63
Issue:
7
Pages:
3756–3762
Publication date:
2020-02-28
Acceptance date:
2020-02-28
DOI:
EISSN:
1520-4804
ISSN:
0022-2623
Language:
English
Keywords:
Pubs id:
1091216
Local pid:
pubs:1091216
Deposit date:
2020-03-05

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